It is widely accepted that there is an accelerated risk for atherosclerosis in diabetic patients. This may result from accelerated non-enzymatic glycation of proteins and lipids and enhanced lipid peroxidation. A major goal of this proposal will be to determine if the susceptibility to oxidation of LDL or HDL or the ability of HDL to protect LDL is altered in NIDDM subjects. If differences are found, then we will attempt to identify factors contributing to thee differences, including studies of subfractions of LDL, and of the levels of activity of lipoprotein associated enzymes that could influence oxidation, including platelet-activating factor- acetylhydrolase (PAF-AH), and paraoxonase. We will also explore the possibility that glycation of LDL and/or HDL also increases its susceptibility to oxidation, both by promoting lipid peroxidation as well as by inactivating PAF-AH and paraoxonase activities. A second major goal will be to see if intensive combinations of antioxidant and dietary interventions can reduce the susceptibility of LDL and HDL to oxidation. This is of practical clinical relevance because previous studies from our laboratory demonstrated that neither vitamin E administration, nor an oleic acid-enriched diet, adequately protected dense LDL subfractions, or HLD from susceptibility to oxidation. Because an enhanced content of dense LDL, and HDL of abnormal composition typify the NIDDM patient, these studies may provide insight into the mechanisms that help to explain the accelerated risk for atherosclerosis seen in diabetic patients, and suggest therapeutic approaches to reduce this risk that could be used in clinical trials to test the oxidation hypothesis.